The basic molecular and cellular mechanisms involved in the regulation of neutrophil (PMN)-mediated inflammation in periodontal disease have yet to be clearly defined. The mission of this program project is to investigate the molecular mechanisms and pathways that regulate production of inflammatory mediators by human neutrophils that contribute to periodontal disease. This program project and its structure was developed in recognition of the interdependence of the elements that initiate and can regulate PMN-derived mediators can serve as templates for design of novel typically active anti-inflammatory agents. A general hypothesis that emerges from our recent experiments and shall be addressed in each project is as follows: In individuals without periodontal disease, down-regulatory bioactive lipids of the host serve as "natural anti-inflammatory local mediators" to prevent harmful PMN responses, thus protecting the periodontal disease. To this end, projects are linked in thematic content and via highly complementary expertise of the investigators. Project #1 (Principal Investigator Charles N. Serhan) will focus on novel lipid mediators generated by PMN. Proposed experiments will highlight receptors and novel signaling molecules that regulate PMN function in vitro and in vivo. Project #2 (Project Leaders T. Van Dyke & J. Badwey) focuses on the role of novel lipid mediators and their stable analogs in regulating the generation of reactive oxygen species by PMN. This project addresses intracellular mechanisms and targets involved in this new pathway. In Project #3, Sean Colgan (Project Leader) will establish the key determinants involved in PMN cross talk pathways with oral epithelial cells and determine their functions in oral epithelial cells. Project #4 (Project Leader N.A. Petasis) will pursue the total synthesis and design of new stable analogs of lipid mediators isolated in this program to establish their structure-function and bioimpact. Conformational studies and new approaches to facilitate syntheses will be evaluate. Studies will utilize patient acquisition, synthesis and demonstration cores to rapidly translate structure to bioimpact. Conformational studies and new approaches to facilitate syntheses will be evaluated. Studies will utilize patient acquisition, synthesis and demonstration cores to rapidly translate structure to bioimpact. Our long-term goals are to elucidate endogenous counter-regulatory mechanisms in inflammation and to provide new therapeutic approaches to periodontal diseases.